Abstract
Bcl-2 overexpression occurs in nearly half of human cancers, and has been associated with radio- and chemoresistance. Here we investigated the potential impact of heavy ions on Bcl-2 overexpressing radioresistant tumors. Whilst Bcl-2 cells (Bcl-2 overexpressing HeLa cells) were more resistant to γ-rays (0.2 keV/µm) and helium ions (16 keV/µm) than Neo cells (neomycin resistant gene-expressing HeLa cells), heavy ions (76-1610 keV/µm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108 keV/µm), which were most effective at reducing the survival among heavy ions tested, decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G2/M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. These findings indicate that high-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be potentially accounted for by the enhanced apoptotic response and prolonged G2/M arrest. We further found that preirradiation treatment with the cell-permeable, small-molecule Bcl-2 inhibitor HA14-1 sensitizes Neo cells and Bcl-2 cells, but not normal human fibroblasts, to carbon ions. These results suggest that HA14-1 preferentially sensitizes tumor cells to heavy ions. Thus, Bcl-2 may be an attractive target for improving the efficacy of heavy-ion therapy.
